Mutual inhibition between quinine and etoposide by human liver microsomes. Evidence for cytochrome P4503A4 involvement in their major metabolic pathways.
The mutual inhibition between quinine and etoposide with their major metabolic pathways (i.e. quinine 3-hydroxylation and etoposide 3'-demethylation) was examined in vitro by human liver microsomes. Etoposide inhibited quinine 3-hydroxylation in a concentration-dependent manner with a mean IC50 of 65 microM. The mean maximum inhibition by etoposide (100 micro) of quinine 3-hydroxylation was about 60%. Similarly, etoposide 3'-demethylation was inhibited by quinine in a concentration-related manner with a mean IC50 value of 90 microM. The mean maximum inhibition by quinine (100 M) of etoposide 3'-demethylation was about 52%. An excellent correlation (r = 0.947, p < 0.01) between quinine 3-hydroxylase and etoposide 3'-demethylase activities in six different human liver microsomes was observed. Two inhibitors of CYP3A4, ketoconazole (1 microM) and troleandomycin (100 microM), inhibited quinine 3-hydroxylation by about 90% and 80%, and etoposide 3'-demethylation by about 75% and 65%, respectively. We conclude that quinine and etoposide mutually inhibit the metabolism of each other, consistent with the previous finding that CYP3A4 catalyzes the metabolism of both substrates.
Zhao
X J
XJ
Department of Clinical Pharmacology, Research Institute, International Medical Center of Japan, Tokyo, Japan.
Kawashiro
T
T
Ishizaki
T
T
D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology*; D005047:Etoposide / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007654:Ketoconazole / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010090:Oxidoreductases, O-Demethylating / Q000037:antagonists & inhibitors; D011802:Quinidine / Q000031:analogs & derivatives / Q000378:metabolism; D011803:Quinine / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D014217:Troleandomycin / Q000494:pharmacology
C013569:3-hydroxyquinidine; D005047:Etoposide; D003577:Cytochrome P-450 Enzyme System; D011803:Quinine; D014217:Troleandomycin; D006899:Mixed Function Oxygenases; D010090:Oxidoreductases, O-Demethylating; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine; D007654:Ketoconazole